Lovastatin

Lovastatin is an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase with IC50 values of 2.3 nmol/L in rat liver cells and 5 nmol/L in the human liver hepatocellular carcinoma cell line, HepG2 [1].

HMG-CoA reductase is responsible for the catalysis of the rate-limiting step in the biosynthesis of cholesterol. It catalyzes the conversion of HMG-CoA to mevalonate, the second step in the production of cholesterol in cells [2].

Lovastatin prevented the proliferation of several cell types by inhibiting the production of mevalonate and its metabolites. Inhibition of mevalonate formation also prevented the production of isoprenoids which are necessary for cell proliferation and other important cell functions. This reduction in isoprenoids caused beneficial pleiotropic effects. Lovastatin caused reduction in DNA synthesis at concentrations of 1 to 20 µM. At 1 µM, it inhibited the increase of mesangial cells in culture. Lovastatin (5 μM) also increased efferocytosis (phagocytosis of apoptotic cells) after 6 hours. However, after 24 hours, its effect was dose-dependent, with a maximum at 10 µM [3, 4, 5].

Mice treated with lovastatin (10 mg/kg) three times over 30 hours showed increased efferocytosis by alveolar macrophages. In a guinea pig wound chamber model, lovastatin (5 µM, 8 days) decreased granulation tissue formation by 64.7% [5, 6].

References:
[1].  Amin D, Gustafson SK, Weinacht JM, et al. RG 12561 (Dalvastatin): A novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent. Pharmacology, 1993, 46(1): 13-22.
[2].  Tobert JA. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nature Reviews Drug Discovery, 2003, 2(7): 517-526.
[3].  Massy ZA, Keane WF, Kasiske BL. Inhibition of the mevalonate pathway: benefits beyond cholesterol reduction. The Lancet, 1996, 347(8994): 102-103.
[4].  O'Donnell MP, Kasiske BL, Kim Y, et al. Lovastatin inhibits proliferation of rat mesangial cells. Journal of Clinical Investigation, 1993, 91(1): 83.
[5].  Morimoto K, Janssen WJ, Fessler MB, et al. Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. The Journal of Immunology, 2006, 176(12): 7657-7665.
[6].  Tan A, Levrey H, Dahm C, et al. Lovastatin induces fibroblast apoptosis in vitro and in vivo: a possible therapy for fibroproliferative disorders. American journal of respiratory and critical care medicine, 1999, 159(1): 220-227.

Lovastatin suppresses the aberrant tau phosphorylation from FTDP-17 mutation and okadaic acid-induction in rat primary neurons.[Pubmed:25770969]

Neuroscience. 2015 May 21;294:14-20.

Statins are a class of cholesterol-lowering drugs and have been suggested therapeutic use for neurodegenerative diseases including Alzheimer's disease (AD). Our recent studies revealed a neuronal protective effect of Lovastatin (LOV) from N-methyl-d-aspartic acid (NMDA) excitotoxicity. The neuroprotective mechanism of statins, however, is far unknown. Here we demonstrated that LOV suppressed the aberrant tau phosphorylation both from frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) mutation and okadaic acid (OA) induction in cultured rat primary neurons. The protective effect of LOV occurred at multiple pathological sites of tau protein, including Tyr181, Tyr231 Ser202/Tyr205, Tyr212/Ser214 and Ser396/Ser404. Further analysis revealed that the potential mechanism of the suppressive effect of LOV resulted from two aspects, activating OA-inhibited protein phosphatase 2A (PP2A) activity and attenuating OA-induced activity of tau kinases CDK5/P25 and CDK2/4, but not glycogen synthase kinase 3beta (GSK3beta). These findings give new insights into the molecular mechanism of LOV-mediated neuroprotective effect and provide experimental evidence for its therapeutic use in AD.

The neuroprotective effect of lovastatin on MPP(+)-induced neurotoxicity is not mediated by PON2.[Pubmed:25842176]

Neurotoxicology. 2015 May;48:166-70.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of the pigmented dopaminergic neurons in the substantia nigra pars compacta with subsequent striatal dopamine (DA) deficiency and increased lipid peroxidation. The etiology of the disease is still unclear and it is thought that PD may be caused by a combination of genetic and environmental factors. In the search of new pharmacological options, statins have been recognized for their potential application to treat PD, due to their antioxidant effect. The aim of this work is to contribute in the characterization of the neuroprotective effect of Lovastatin in a model of PD induced by 1-methyl-4-phenylpyridinium (MPP(+)). Male Wistar rats (200-250 g) were randomly allocated into 4 groups and administered for 7 days with different pharmacological treatments. Lovastatin administration (5 mg/kg) diminished 40% of the apomorphine-induced circling behavior, prevented the striatal DA depletion and lipid peroxides formation by MPP(+) intrastriatal injection, as compared to the group of animals treated only with MPP(+). Lovastatin produced no change in paraoxonase-2 (PON2) activity. It is evident that Lovastatin conferred neuroprotection against MPP(+)-induced protection but this effect was not associated with the induction of PON2 in the rat striatum.

Prevention of phenytoin-induced gingival overgrowth by lovastatin in mice.[Pubmed:25843680]

Am J Pathol. 2015 Jun;185(6):1588-99.

Drug-induced gingival overgrowth is caused by the antiseizure medication phenytoin, calcium channel blockers, and ciclosporin. Characteristics of these drug-induced gingival overgrowth lesions differ. We evaluate the ability of a mouse model to mimic human phenytoin-induced gingival overgrowth and assess the ability of a drug to prevent its development. Lovastatin was chosen based on previous analyses of tissue-specific regulation of CCN2 production in human gingival fibroblasts and the known roles of CCN2 in promoting fibrosis and epithelial to mesenchymal transition. Data indicate that anterior gingival tissue overgrowth occurred in phenytoin-treated mice based on gross tissue observations and histomorphometry of tissue sections. Molecular markers of epithelial plasticity and fibrosis were regulated by phenytoin in gingival epithelial tissues and in connective tissues similar to that seen in humans. Lovastatin attenuated epithelial gingival tissue growth in phenytoin-treated mice and altered the expressions of markers for epithelial to mesenchymal transition. Data indicate that phenytoin-induced gingival overgrowth in mice mimics molecular aspects of human gingival overgrowth and that Lovastatin normalizes the tissue morphology and the expression of the molecular markers studied. Data are consistent with characterization of phenytoin-induced human gingival overgrowth in vivo and in vitro characteristics of cultured human gingival epithelial and connective tissue cells. Findings suggest that statins may serve to prevent or attenuate phenytoin-induced human gingival overgrowth, although specific human studies are required.

Lovastatin production: From molecular basis to industrial process optimization.[Pubmed:25868803]

Biotechnol Adv. 2015 Nov 1;33(6 Pt 1):648-65.

Lovastatin, composed of secondary metabolites produced by filamentous fungi, is the most frequently used drug for hypercholesterolemia treatment due to the fact that Lovastatin is a competitive inhibitor of HMG-CoA reductase. Moreover, recent studies have shown several important applications for Lovastatin including antimicrobial agents and treatments for cancers and bone diseases. Studies regarding the Lovastatin biosynthetic pathway have also demonstrated that Lovastatin is synthesized from two-chain reactions using acetate and malonyl-CoA as a substrate. It is also known that there are two key enzymes involved in the biosynthetic pathway called polyketide synthases (PKS). Those are characterized as multifunctional enzymes and are encoded by specific genes organized in clusters on the fungal genome. Since it is a secondary metabolite, cultivation process optimization for Lovastatin biosynthesis has included nitrogen limitation and non-fermentable carbon sources such as lactose and glycerol. Additionally, the influences of temperature, pH, agitation/aeration, and particle and inoculum size on Lovastatin production have been also described. Although many reviews have been published covering different aspects of Lovastatin production, this review brings, for the first time, complete information about the genetic basis for Lovastatin production, detection and quantification, strain screening and cultivation process optimization. Moreover, this review covers all the information available from patent databases covering each protected aspect during Lovastatin bio-production.

Lovastatin inhibits transforming growth factor-beta1 expression in diabetic rat glomeruli and cultured rat mesangial cells.[Pubmed:10616843]

J Am Soc Nephrol. 2000 Jan;11(1):80-7.

Diabetic nephropathy is a leading cause of end-stage renal disease and is characterized by excessive deposition of extracellular matrix (ECM) proteins in the glomeruli. Transforming growth factor-beta (TGF-beta) is the major mediator of excessive accumulation of ECM proteins in diabetic nephropathy through upregulation of genes encoding ECM proteins as well as downregulation of genes for ECM-degrading enzymes. It has been shown that Lovastatin, an inhibitor of 3-hydroxy3-methylglutaryl CoA reductase, delays the onset and progression of different models of experimental nephropathy. To evaluate the effect of Lovastatin on the development and progression of diabetic nephropathy, streptozotocin-induced diabetic rats were studied for 12 mo. In untreated diabetic rats, there were significant increases in blood glucose, urine albumin excretion, kidney weight, glomerular volume, and TGF-beta1 mRNA expression in the glomeruli compared with normal control rats treated with citrate buffer only. Treatment with Lovastatin in diabetic rats significantly suppressed the increase in urine albumin excretion, kidney weight, glomerular volume, and TGF-beta1 mRNA expression despite high blood glucose levels. To elucidate the mechanisms of the renal effects of Lovastatin, rat mesangial cells were cultured under control (5.5 mM) or high (30 mM) glucose with Lovastatin alone, mevalonate alone, or with both. Under high glucose, TGF-beta1 and fibronectin mRNA and proteins were upregulated. These high glucose-induced changes were suppressed by Lovastatin (10 micro/M) and nearly completely restored by mevalonate (100 microM). These results suggest that Lovastatin has a direct cellular effect independent of a cholesterol-lowering effect and delays the onset and progression of diabetic nephropathy, at least in part, through suppression of glomerular expression of TGF-beta1.

Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest and apoptosis.[Pubmed:10652602]

Anticancer Res. 1999 Jul-Aug;19(4B):3133-40.

An inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, Lovastatin, induces growth arrest and cell death in a wide variety of malignant cells in vitro. We analyzed the effect of Lovastatin on myeloid leukemic cell lines. Lovastatin significantly inhibited the proliferation of 7 cell lines among 11 myeloid leukemic cell lines in a dose-dependent manner. In order to address the mechanism of antileukemic effect of Lovastatin, cell cycle analysis was attempted in HL-60 cells, showing that Lovastatin induced G1 arrest in HL-60 cells following 72 h of drug exposure (1.5 microM, 5 microM and 10 microM) in a dose-dependent manner. Analysis of G1 regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase (CDK) 2, CDK4, CDK6 and cyclin E were decreased after treatment with Lovastatin (10 microM) in a time-dependent manner, but not cyclin D1. In addition, Lovastatin increased the protein level of the cyclin-dependent kinase inhibitor (CDKI), p27, and markedly enhanced the binding of p27 with CDK2 and CDK4 more than CDK6 after 24 h exposure. At higher doses of Lovastatin (50 mM, 100 mM, 200 mM), a significant apoptosis was observed as evidenced by FACS analysis with annexin V staining, which was associated with downregulation of Bcl-2 protein. These results suggest that Lovastatin inhibits the proliferation of myeloid leukemic cells via G1 arrest in association with p27 induction and is an effective inducer of apoptosis in HL-60 cells.

Discovery, biochemistry and biology of lovastatin.[Pubmed:3055919]

Am J Cardiol. 1988 Nov 11;62(15):10J-15J.

Cholesterol is a 27-carbon steroid that is an essential component of the cell membrane, the immediate precursor of steroid hormones, the substrate for the formation of bile acids, and is required for the assembly of very low density lipoprotein in the liver. Because as much as two-thirds of total body cholesterol in patients is of endogenous origin, an effective means to control cholesterogenesis may occur by inhibition of its biosynthesis. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involve the formation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). Early attempts to pharmacologically block cholesterol synthesis focused only on steps later in the biosynthetic pathway and resulted in compounds with unacceptable toxicity. Recent research had identified that HMG CoA reductase is a key rate-limiting enzyme in this pathway and is responsible for the conversion of HMG CoA to mevalonate. Additional research with fungal metabolites identified a series of compounds with potent inhibiting properties for this target enzyme, from which Lovastatin was selected for clinical development. A reduction in cholesterol synthesis by Lovastatin has been subsequently confirmed in cell culture, animal studies and in humans. A resultant decrease in circulating total and low-density lipoprotein (LDL) cholesterol has also been demonstrated in animals and humans. Because hepatic LDL receptors are the major mechanism of LDL clearance from the circulation, further animal research has confirmed that these declines in cholesterol are accompanied by an increase in hepatic LDL receptor activity. Lovastatin effectively diminishes endogenous cholesterol synthesis providing useful therapeutic properties for patients with hypercholesterolemia.

Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.[Pubmed:6933445]

Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957-61.

Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.